Identification of loss-of-function HOXA2 mutations in Chinese families with dominant bilateral microtia

Si, Nuo; Meng, Xiangzhi; Lu, Xiaosheng; Zhao, Xuelian; Li, Chuan; Yang, Ming; Zhang, Ye; Wang, Changchen; Guo, Peipei; Zhang, Xue; Pan, Bo; Jiang, Haiyue

doi:10.1016/j.gene.2020.144945

Cited by 19 publications

(16 citation statements)

References 23 publications

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“…Homeobox genes participate in the formation of the pharyngeal arches. 4,41 They encode transcription factors that determine cell positional identity and morphogenesis during development, as well as switch on cascades of other genes that shared a 180 bp segment of DNA. 1,4,[41][42][43] The Hox gene family was discovered to be grouped inside the genome and ordered on the chromosome in the order of expression during development.…”

Section: Discussionmentioning

confidence: 99%

“…4,41 They encode transcription factors that determine cell positional identity and morphogenesis during development, as well as switch on cascades of other genes that shared a 180 bp segment of DNA. 1,4,[41][42][43] The Hox gene family was discovered to be grouped inside the genome and ordered on the chromosome in the order of expression during development. This ordered pattern of gene expression could be part of a mechanism that generates morphogenetic specification.…”

Section: Discussionmentioning

confidence: 99%

“…This ordered pattern of gene expression could be part of a mechanism that generates morphogenetic specification. 4,41 HoxA2, a member of the HOXA cluster, encodes a protein with a molecular weight of 41kD and is important in the regulation of development and morphogenesis in patterning the antero-posterior axis of the embryo of almost all metazoans such as in patterning and morphogenesis of the neural-crest-derived mesenchyme.…”

Section: Discussionmentioning

confidence: 99%

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The role of genetic factors in microtia: A systematic review

Putri

Stephanie²,

Pramanasari³

et al. 2022

F1000Res

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Background: Microtia is a congenital malformation of the outer ears caused by improper embryonic development. The origin of microtia and causes of its variations remain unknown. Because of the lack of clarity regarding the role of genetic variables in microtia, we conducted a systematic review to qualitatively identify the genes most important in the development of microtia to provide an up-to-date review. Methods: Using six search engines, we searched all published studies related to the genetic factors of isolated microtia and syndromic microtia. The identified publications were screened and selected based on inclusion and exclusion criteria by the authors and assessed for methodological quality using the Joanna Briggs Institute (JBI) critical appraisal tools. We found 40 studies, including 22 studies on syndromic microtia and 18 studies on isolated microtia. Data extraction of each study was arranged in tabulation for syndromic and isolated microtia. The extracted data were: first author’s surname, year of publication, country of origin, study design, sample characteristic and gene assessed. Results: After the data were extracted, analyzed, and reviewed, the most common gene suspected to be involved in isolated microtia was Homeobox A2 (HOXA2, 12.1%). Conversely, in syndromic microtia, the two most common genes supposed to play a role were Fibroblast Growth Factor 3 (FGF3, 47.2%) and Treacher–Collins–Franceschetti syndrome 1 (TCOF1, 30.2%). From the studies, the three most prevalent genes associated with microtia were HOXA2 (10%), FGF3 (8.4%), and TCOF1 (5.4%). In syndromic microtia, the most common mutation types were deletion in TCOF1 (46.9%) and missense and deletion in FGF3 (both 38%), and in isolated microtia, the most common mutation type was silent in HOXA2 (54.2%). Conclusions: In summary, genetic factors are involved in microtia; thus, molecular analysis is strongly advised. PROSPERO registration: CRD42021287294 (25/10/21).

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The role of genetic factors in microtia: A systematic review

Putri

Stephanie²,

Pramanasari³

et al. 2022

F1000Res

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“…Of these, the specifically interesting locus is the one situated in the homeobox A2 ( HOXA2 ) gene, which encodes a transcription factor that is important during embryonic development. HOXA2 locates in chromosome 7, has a role in the development of the lower and middle part of the face and middle ear, and its deficiency have been associated with ear microtia (reviewed in [ 46 ]). Comb-p is a flexible tool specifically for meta-analysed EWAS summary statistics as it uses P-values by sliding windows and takes into account the correlation between near-by sites; however, comb-p has been shown to produce false-positive results, especially if the signal in the original data was weak [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Maternal haemoglobin levels in pregnancy and child DNA methylation: a study in the pregnancy and childhood epigenetics consortium

et al. 2021

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Altered maternal haemoglobin levels during pregnancy are associated with pre-clinical and clinical conditions affecting the fetus. Evidence from animal models suggests that these associations may be partially explained by differential DNA methylation in the newborn with possible long-term consequences. To test this in humans, we meta-analyzed the epigenome-wide associations of maternal haemoglobin levels during pregnancy with offspring DNA methylation in 3,967 newborn cord blood and 1,534 children and 1,962 adolescent whole-blood samples derived from 10 cohorts. DNA methylation was measured using Illumina Infinium Methylation 450K or MethylationEPIC arrays covering 450,000 and 850,000 methylation sites, respectively. There was no statistical support for the association of maternal haemoglobin levels with offspring DNA methylation either at individual methylation sites or clustered in regions. For most participants, maternal haemoglobin levels were within the normal range in the current study, whereas adverse perinatal outcomes often arise at the extremes. Thus, this study does not rule out the possibility that associations with offspring DNA methylation might be seen in studies with more extreme maternal haemoglobin levels.

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“…Variant fully explaining the patient's whole phenotype was named full-type variant. Furthermore, variant explains part of the patient's phenotype, eg nonsense HOXA2 mutation in a patient with microtia, atrial septal defect and lung hypoplasia, or partially explains a phenotype 17,18 eg nonsense HOXA2 mutation in a patient with microtia whose other variant is a definitively pathogenic variant in mixed-lineage leukemia 2 (Kabuki syndrome). 19 There might be discrepancies between the results of this study and the actual results due to some variants without information about pathogenicity, but it was clear that the pathogenic variants had a greater influence on the phenotype of the patients.…”

Section: Disscusionmentioning

confidence: 99%

Heterogeneity of Accompanying Phenotypes and Genomic Variants Involved in Microtia

Huang

Guo

et al. 2021

Journal of Craniofacial Surgery

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Objectives: The symptoms associated with microtia are everchanging and not to stick to 1 pattern. The symptoms associated with microtia are constantly changing and are not set in stone. The aim of this article was to describe the various phenotypes from multiple systems found in microtitis patients included in the Data-basE of genomiC varIation and Phenotype in Humans using Ensembl Resources database, and to analyze possible pathogenic mutations. Methods: DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources is an interactive web-based database, which incorporates a suite of tools designed to aid the interpretation of genomic variants. The term ''microtia'' was used as the search term, and the data extracted from the DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources for this study was updated until October 2020. Pearson chi-squared test was used to test associations between types of genomic variants and the pathogenicity of variants. Results: Of the 386 cases enrolled in the study, 99% (n ¼ 382) had 1 or more associated abnormalities. The most frequently detected abnormalities were those of the face and neck (n ¼ 362 [93.8% of all cases]); musculoskeletal system (n ¼ 337 [87.3%]); and nervous system (n ¼ 334 [86.5%]), followed by abnormalities of limbs (n ¼ 252 [65.3%]); the eye (n ¼ 212 [54.9%]); and the integument (n ¼ 200 [51.8%]). Besides, a total of 479 genomic variants were determined, including sequence variants and copy number variants (loss and gain). The pathogenicity of loss-type variants was significantly higher among other types (P < 0.001). Twelve sharing variants had more than 5 repeats, and the repeated fragments were concentrated on chromosome 3, 7, 9, 10, 11, 15, 17, 18, and 22. Conclusions: Identification of the relation between phenotypes and genotypes will facilitate the uncovering of the mechanism of microtia and the study of potential therapeutic targets.

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Identification of loss-of-function HOXA2 mutations in Chinese families with dominant bilateral microtia

Cited by 19 publications

References 23 publications

The role of genetic factors in microtia: A systematic review

The role of genetic factors in microtia: A systematic review

Maternal haemoglobin levels in pregnancy and child DNA methylation: a study in the pregnancy and childhood epigenetics consortium

Heterogeneity of Accompanying Phenotypes and Genomic Variants Involved in Microtia

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